Abstract
The relationship between primary biliary cholangitis (PBC), a chronic cholestatic autoimmune liver disease, and the peripheral immune system remains to be fully understood. Herein, we performed the first mass cytometry (CyTOF)-based, immunophenotyping analysis of the peripheral immune system in PBC at single-cell resolution. CyTOF was performed on peripheral blood mononuclear cells (PBMCs) from PBC patients (n = 33) and age-/sex-matched healthy controls (n = 33) to obtain immune cell abundance and marker expression profiles. Hierarchical clustering methods were applied to identify immune cell types and subsets significantly associated with PBC. Subsets of gamma-delta T cells (CD3+TCRgd+), CD8+ T cells (CD3+CD8+CD161+PD1+), and memory B cells (CD3−CD19+CD20+CD24+CD27+) were found to have lower abundance in PBC than in control. In contrast, higher abundance of subsets of monocytes and naïve B cells were observed in PBC compared to control. Furthermore, several naïve B cell (CD3−CD19+CD20+CD24−CD27−) subsets were significantly higher in PBC patients with cirrhosis (indicative of late-stage disease) than in those without cirrhosis. Alternatively, subsets of memory B cells were lower in abundance in cirrhotic relative to non-cirrhotic PBC patients. Future immunophenotyping investigations could lead to better understanding of PBC pathogenesis and progression, and also to the discovery of novel biomarkers and treatment strategies.
Highlights
The relationship between primary biliary cholangitis (PBC), a chronic cholestatic autoimmune liver disease, and the peripheral immune system remains to be fully understood
We aimed to evaluate the use of mass cytometry to immunophenotype stored peripheral blood mononuclear cells (PBMCs) collected from PBC patients and healthy subjects in order to study differences in immune cell subsets, as well as to inform future studies utilizing our extensive biobank blood collections
PBMCs were collected from 33 female PBC patients and 33 age-/sex-matched controls, and subjected to single-cell mass cytometry (CyTOF) to obtain immune cell abundance profiles
Summary
The relationship between primary biliary cholangitis (PBC), a chronic cholestatic autoimmune liver disease, and the peripheral immune system remains to be fully understood. A number of studies focused on peripheral immunity in PBC have reported alterations in various immunological subsets including natural killer (NK) cells[7], regulatory T c ells8, CD8+CD57+ T c ells[9] and mucosal-associated invariant T (MAIT) cells[10] To what extent these differences reflect ongoing liver pathology, or directly implicate pathological subsets, remains to be determined. Mass cytometry is an emerging platform for immunophenotyping that overcomes key limitations of traditional fluorescence-based flow c ytometry[11,12] This technology utilizes heavy-metal ion tags instead of fluorophores to detect target-bound monoclonal antibodies, allowing for simultaneous quantification of 40 or more cell markers[11]. This increased dimensionality facilitates a more comprehensive survey of immune composition and has recently been employed in the examination of peripheral blood in various pathologies, including autoimmune diseases and cancers[12,13,14]
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